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Deciphering DNA, Top Speed

Helicos BioSciences and sequencing.

The sequencing of the human genome is one of biotech’s greatest technical achievements to date. But some biomedical researchers argue that they won’t truly understand how genes contribute to health and disease – and so won’t be able to turn genomic knowledge into new cures and treatments – until they can compare, letter by letter, the DNA sequences of thousands of sick and healthy people. And that is just not possible with today’s technology; using about 100 state-of-the-art sequencing machines to fully sequence the 3.2 billion DNA letters that make up one person’s genome would take six months and cost $20 million to $30 million.

A few companies, however, are close to commercializing technologies that could begin to chip away at the high cost of decoding genomes. Among them is one-year-old startup Helicos BioSciences, located in Cambridge, MA. Using technology developed by Stephen Quake, a Stanford University biophysicist, and with $27 million in venture capital funding, Helicos is currently building its first sequencing machine. The company intends to place the device in an academic lab for testing by the end of the year. Helicos’s first commercial sequencing machines will be ready for sale by the end of 2006 or early 2007, says president and CEO Stan Lapidus.

Helicos’s technology eliminates many of the expensive and time-­consuming steps that are central to conventional DNA sequencing. The machine works, in essence, by photographing the process of DNA replication.

Technicians chop up the DNA to be sequenced into short pieces just a few hundred letters long and split each piece into single strands, which will serve as templates for new DNA copies. They take about 1.2 billion of those templates and chemically anchor them side by side, like tiny bristles, on a glass slide. The Helicos machine then washes the slide with DNA-synthesizing enzymes and fluo­rescently tagged versions of the DNA bases – the molecular building blocks represented by the familiar DNA letters. It introduces copies of just one base at a time; wherever a template strand calls for that letter in the next open position, the enzymes incorporate it into the growing DNA copy. The machine then washes out the extra, unincorporated bases and takes a picture that reveals the newly incorporated bases as dots of lights. Once it has captured an image, the device pumps in chemicals that stop the new bases from glowing, in preparation for another cycle of washes and photos.

The Helicos machine repeats the whole process over and over, building up the new DNA copies one letter at a time. A computer analyzes all the captured images to determine the sequence of each short strand; then, using the published human genome sequence as a guide, it pieces all the short sequences together into a single complete one. When Helicos’s commercial machine is released, says Lapidus, it will sequence a whole genome start to finish in three days and for a cost of $5,000.

Helicos’s basic approach to sequencing, called “sequencing by synthesis,” is not unique. But what makes the com­pany’s system different from others under development is that it doesn’t require that the sample DNA be copied many thousands of times before sequencing. Skipping the copying step translates into easier pre­paration of samples and lower costs, says Harvard genetics professor George Church, who consults for Helicos. But, he adds, it’s not clear yet just how much those advantages will matter in the end. “It’s a benefit,” he says. “It’s just a matter of how big.”

And while the magnitude of Helicos’s technical advantage remains unclear, what is certain is that the company will have to play catch-up on the path to commercialization. Two other companies – 454 Life Sciences, based in Branford, CT, and Solexa, based in Essex, England – each have at least four more years’ experience in developing low-cost sequencing. Both 454 and Solexa are gearing up to market their first commercial units this year. “Speed to market is very important in this area,” says Tony Smith, Solexa’s vice president and chief scientific officer. Helicos will have to figure out the most efficient way of building its machines and proving the technology’s value to customers. And by the time the startup does get its machines out the door, it will likely face a tough fight with the more established companies for its share of what’s shaping up to be an important and competitive market.

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